Control of erythroid cell production via caspase-mediated cleavage of transcription factor SCL/Tal-1

Abstract

SCL/Tal-1 is a helix-loop-helix (HLH) transcription factor required for blood cell development, whose abnormal expression is responsible for induction of T-cell acute lymphoblastic leukemia. We show here that SCL/Tal-1 is a key target of caspases in developing erythroblasts. SCL/Tal-1 degradation occurred rapidly after caspase activation and preceded the cleavage of the major erythroid transcription factor GATA-1. Expression of a caspase-resistant SCL/Tal-1 in erythroid progenitors was able to prevent amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis induced by growth factor deprivation or death receptor triggering. The potent proerythropoietic activity of uncleavable SCL/Tal-1 was clearly evident in the absence of erythropoietin, a condition that did not allow survival of normal erythroid cells or expansion of erythroblasts expressing caspase-resistant GATA-1. In the absence of erythropoietin, cells expressing caspase-resistant SCL/Tal-1 maintain high levels of Bcl-X L , which inhibits amplification of the caspase cascade and mediates protection from apoptosis. Thus, SCL/TAL-1 is a survival factor for erythroid cells, whereas caspase-mediated cleavage of SCL/Tal-1 results in amplification of caspase activation, GATA-1 degradation and impaired erythropoiesis.

Twist is substrate for caspase cleavage and proteasome-mediated degradation

“…This is reminiscent of what was recently reported about another member of the bHLH family of transcription factors, SCL/Tal-1, which regulates hematopoietic cell survival and differentiation through a caspase-mediated process. 62,63 Finally, the Twist protein has been reported to be accumulated in sarcomas, lymphomas and certain types of carcinomas, [18][19][20] while unstable forms of Twist have often been detected in Saethre-Chotzen patients. 49 In both instances, the biochemical bases for the altered expression of Twist are presently unknown.…”

Anticancer activity of a synthetic peptide derived from harmoniasin, an antibacterial peptide from the ladybug Harmonia axyridis

“…Since apoptosis can proceed via either caspase-dependent or -independent signaling pathways (26,27), the involvement of caspases in HaA4-induced leukemia cell apoptosis was assessed. As shown in Fig.…”

Apoptotic mechanisms in the control of erythropoiesis

“…The transduction in hemopoietic progenitors of a Tal-1 mutant resistant to caspase cleavage protected erythroid cells from Fas-mediated inhibitory effect on erythroid maturation and cleavage of GATA-1. 88 Interestingly, the expression of the Tal-1 caspase-resistant mutant in erythroid cells completely protects these cells from the apoptosis elicited by erythropoietin deprivation. 88 The ensembling of these observations indicates that the apoptotic effects and the inhibitory actions on cell differentiation elicited by Epo deprivation or by death receptor triggering involve as a necessary step the caspase-mediated cleavage of two transcription factors, Tal-1 and GATA-1, whose integrity and activity are essential for erythroid maturation and survival ( Figure 7).…”

“…88 Interestingly, the expression of the Tal-1 caspase-resistant mutant in erythroid cells completely protects these cells from the apoptosis elicited by erythropoietin deprivation. 88 The ensembling of these observations indicates that the apoptotic effects and the inhibitory actions on cell differentiation elicited by Epo deprivation or by death receptor triggering involve as a necessary step the caspase-mediated cleavage of two transcription factors, Tal-1 and GATA-1, whose integrity and activity are essential for erythroid maturation and survival ( Figure 7). 70 have shown that erythroid cells, in addition to Fas and TNF-R1, also express other death receptors, such as TRAIL-R1 and TRAIL-R2.…”